Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast
Advances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast S...
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The Company of Biologists
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doaj-0d7eed35730249099d13592cfce5a5212020-11-25T03:58:59ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112020-07-0113710.1242/dmm.044560044560Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeastBarry P. Young0Kathryn L. Post1Jesse T. Chao2Fabian Meili3Kurt Haas4Christopher Loewen5 Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada Advances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in a high-throughput fashion through simple growth assays using solid or liquid media. Sentinel interaction mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor gene PTEN as an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants.http://dmm.biologists.org/content/13/7/dmm044560yeastvariantshuman disease genes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Barry P. Young Kathryn L. Post Jesse T. Chao Fabian Meili Kurt Haas Christopher Loewen |
spellingShingle |
Barry P. Young Kathryn L. Post Jesse T. Chao Fabian Meili Kurt Haas Christopher Loewen Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast Disease Models & Mechanisms yeast variants human disease genes |
author_facet |
Barry P. Young Kathryn L. Post Jesse T. Chao Fabian Meili Kurt Haas Christopher Loewen |
author_sort |
Barry P. Young |
title |
Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
title_short |
Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
title_full |
Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
title_fullStr |
Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
title_full_unstemmed |
Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
title_sort |
sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2020-07-01 |
description |
Advances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in a high-throughput fashion through simple growth assays using solid or liquid media. Sentinel interaction mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor gene PTEN as an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants. |
topic |
yeast variants human disease genes |
url |
http://dmm.biologists.org/content/13/7/dmm044560 |
work_keys_str_mv |
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